Tivozanib (also known as AV-951 and KRN951) is a potent and selective small-molecule inhibitor of VEGF receptors 1, 2 and 3. Tivozanib exhibits picomolar inhibitory activity against all three receptors, and it exhibits antitumor activity in preclinical models (Nakamura et al., 2006, Cancer Res. 66:9134-9142). Tivozanib has yielded positive interim results in a 272-patient Phase 2 clinical trial (Bhargava et al., 2009, ASCO Annual Meeting Proceedings, Vol 27, No. 15s, Abstract No. 5032). The most common side effects associated with tivozanib treatment in Phase 1 and Phase 2 clinical trials are hypertension and dysphonia.
Mammalian target of rapamycin, commonly known as mTOR (also known as FRAP, RAFT1 and RAP1) is a kinase that acts downstream of activated PI3K. Several specific inhibitors of mTOR are known, including rapamycin, temsirolimus, everolimus and OSI-027. In recent years, temsirolimus (TORISEL®; also known as CCI-779) and everolimus (AFINITOR®; also known as RAD-001) have received FDA marketing approval as monotherapies for renal cell carcinoma. As a monotherapy, temsirolimus typically is administered by intravenous infusion on a weekly schedule. The side effects of temsirolimus can be severe, including severe allergic reactions, black or bloody stools, calf pain, chest pain, cough, difficult or painful urination, irregular heartbeat, fever, chills, breathing problems, severe headache, severe stomach pain or diarrhea, ulceration of mucous membranes, severe tiredness or weakness, swelling of the hands, feet or ankles, and symptoms of high blood sugar.
With any drug, optimal dosage involves balancing the desired therapeutic effect against unwanted side effects, i.e., drug toxicities. The dosage range that yields a therapeutic effect with an acceptable side effect profile is known as the therapeutic window. When two drugs are used in combination, the situation with respect to therapeutic window can become complicated and unpredictable. The therapeutic effects of the two drugs can be non-additive, additive or synergistic. Similarly, the unwanted side effects, i.e., the drug toxicities, can be non-additive, additive or synergistic.
Although the prior art contains suggestions regarding the theoretical advantages of a combination therapy involving a VEGF tyrosine kinase inhibitor and an mTOR inhibitor, the combination of a VEGF tyrosine kinase inhibitor and temsirolimus has been problematic, because of toxicity of the combination. To date, no combination of a VEGF tyrosine kinase inhibitor with temsirolimus has been found clinically tolerable at the respective individual maximum tolerated dosages (MTDs) of the drugs. For example, in 2007, Patnaik et al. reported that the combination of sorafenib and temsirolimus resulted in “significant mucocutaneous toxicity at full doses of sorafenib” (Patnaik et al., ASCO Annual Meeting Proceedings Part I, Vol. 25, No. 18S (June 20 Supplement), 2007:3512). In 2009, Patel et al., reported dose-limiting toxicities in two out of three patients in the first cohort of patients in a trial to determine the MTDs of the sunitinib and temsirolimus in combination to treat advanced renal cell carcinoma (Patel et al., 2009, Clinical Genitourinary Cancer 7:24-27). Based on this study, Patel et al. concluded: “Concomitant use of IV temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.” In a 2009 review article, Sosman et al. state that the combination of temsirolimus with sorafenib has required dose reductions, and that temsirolimus and sunitinib “are not safe to be given together” (Sosman et al., 2009, Cancer 115:2368-2375, at 2371).